Preparation of sulphanilamidopyridines



Patented June 10, 1941 PREPARATION or SULPHANILAMIDO- rmmmas Elmore H.Northey, Bound Brook, and Martln E. Hultquist, North Plainfleld, N. J.,assignors, by mesne assignments, to American Cyanamid Company, New York,N.

Maine Y., a corporation of No Drawing. Application July 22, 1939, SerialNo. 285,968

3 Claims.

This invention relates to sulphanilamidopyridines andnitrosulphonamidopyridines and processes of preparing them.

The compounds of the present invention have the following generalformula:

in which X is either hydrogen or an alkali metal and R is an amino,acylamino or 9. nitro group.

The process of the present invention is an improved method ofpreparation. when R is an amino or acylamino group, such compounds beingknown heretofore. However, when R is a n'itro group, the compounds arenew and as such are not limited to the method of preparation of thepresent invention.

The past methods for the production of sulpharilamidopyridines haveusually resulted in only moderately good yields. For example, theprocess wherein Z-aminopyridine was reacted: with N-acetylsulphanilylchloride in slightly alkaline aqueous solutions to form 2-(N-acetylsulphanilamido)-pyridine which was subsequently hydrolyzed in astrong aqueous sodium hydroxide solution to produce the2-su-lphanilarnidopyridine resulted in a product of good quality but theyield was generally only about 40% of the theoretical based on thequantity of the 2-aminopyridine used. When a tertiary alkyl aminesolution was used for the first part of the reaction instead of theaqueous alkaline solution, the yields were increased to about 50% of thetheoretical. These aqueous alkaline solutions or tertiary alkyl aminesolutions act as solvents for the 2-aminopyridine but are not goodsolvents for the N-acetylsulphanilyl chloride or the reaction product2-(N acetylsulphanilarnido)-pyridine. Therefore, the reaction must takeplace in a heterogeneous sys tem and the precipitated reaction productrequires filtration prior to hydrolysis to the sulphanilamidopyridine.

According to the present invention, we have found that improved yieldsand a better quality sulphanilamidopyridine is obtained when thereactions take place in the presence of dioxane which we have found tobe a solvent for both the reacting substances and also of the reactionproduct.

We have found that yields as high as 95% of the theoretical based on theacetylsulphanilyl chloride are obtained when dioxane is used with excess2-aminopyridine.

When'the invention is carried out according to the preferred method,about 01'. the solvent is recovered and can be used over and over again.This is of economic importance because it' materially aids in reducingthe cost of production. The crude product obtained by this improvedmethod is usually a much higher grade substance than the crude productof past procedures and therefore requires fewer steps in thepurification process. This is an important factor as one of the mostimportant fields for these compounds is in chemotherapy.

The present invention is therefore an improvement over prior processesnot only because it results in improved yields ofsulphanilamidopyridines in purer form but also because it results in alowered cost of production by incorporating labor and time savingfeatures which eliminate certain intermediate steps.

The present invention will be illustrated by the use of the followingspecific examples but is not to be limited thereto.

Example 1 47 parts (0.5 mol) of 2-aminopyridine were dissolved in 200parts dry dioxane. 58.5 parts (0.25 mol) of dry N-acetylsulphanilylchloride were added under agitation and the mixture heated to 95 C. for15 minutes. The mixture separated into two layers while warm. 0n coolingunder agitation, crystallization occurred. The mass was filtered andwashed well with water. The dry weight of 2-(N -acetylsulphanilamido)-pyridine was 108 parts or 92.8% of theory based on theN-acetylsulphanilyl chloride used. It was practically pure as indicatedby a melting range of 222 224.5 C. and assay of 100.3%. The color waswhite where previous methods of synthesis gave a crude product having ayellow or brown color and much lower melting range.

The product as prepared above was hydrolyzed by boiling with 2.5 molesof caustic soda per mole of 2-(N -acetylsulphanilamido-pyridine inaqueous solution. On acidification of the hydrolyzed mixture,Z-mlphanilamidopyridine was obtained in almost quantitative yield. Thecrude product was white and required butone recrystallization to be ofmedicinal quality.

Example 2 94 parts of 2-aminopyridine (1 mole) was dissolved in 400parts of dry dioxane arid 110.8 parts 2 -i or p-nitrobenzenesulphonylchloride added. The

temperature was raised to 95 C. and held for 15 minutes.

water. The dried weight was 116.5 parts or of theory. The material wasrecrystallized from 80% diox'ane. It crystallized as light yellowneedles or prisms which melt with decomposition indefinitely above 170C. depending on the rate of heating. The soluble alkali metal salts maybe prepared by treating with an'alkali metal-acetylsuiphaniiamido)-pyridine, if desired, may

be obtained as a final product and need not necessariiy be hydrolyzed tothe 2-sulphanilamidopyridine The di-(sulphanilamido) -pyridines may beprepared according to the present process by sub- The mixture wasdiluted with 400 parts p of hot water. When crystallization was completethe mixture was filtered and washed well with stitution o1diaminopyridines or the amino pyridines in the examples as given.

I The present invention is not limited to the use of N-acetylsulphanilylchloride as one of its reacting substances but may use other acylderiva-- tives such as N-propionylsulphanilyl chloride,

When it is desired to use the sulphaniiamidopyridine andp-nitrobenzenesulphonamidopyridines of the present invention in asoluble form, this may be accomplished by preparing them in the form oftheir salts with the alkali metals.

It is claimed:

1. A method of preparing compounds included i in the group consisting ofsulphanilamidopyri dines and p-nitrobenzenesulphonamidopyridines whichincludes the step of reaction an aminopyridine with a compound selectedfrom the group consisting 0'1 N-acylsulphanilyl chlorides andp-nitrobenzenesuiphonyi chlorides in the presence of dioxane.

2. A method of preparing sulphanilamidopyridine compounds whichcomprises reacting an aminopyridine with an N-acylsuiphanilyl chloridein the presence of dioxane.

3. A method of preparing a 2-sulphanilamidopyridine which comprisesreacting an N-acylsuiphanilyl chloride with 2-aminopyridine in dioxane.

ELMORE H. NORTHEY. MARTIN E. HULTQUIST.

CERTIFICATE OF CORRECTION.

Patent No. 2,245,292. June 10, 19m.

ELMORE H. NORTHEY, ET AL.

It is hereby certified that error appears in the printed specificationof the above numbered patent requiring correction as follows: Page 2,sec- 0nd column, line 16, claim 1, for "reaction" read "reacting"; andthat the said Letters Patent should be read withthis correction thereinthat the same may conform to the record of the case in the PatentOffice.

Signed and sealed this 5th day of August, A. D. 191:,1.

Henry Van Arsdale,

(Seal) I Acting Commissioner of Patent s.

